Papaverine monopyridoxal phosphate

ABSTRACT

An addition complex of Papaverine, namely Papaverine monopyridoxal phosphate, is described, as well as its preparation. The compound has utility in the fields of neurology, cardiology and arterial pathology.

Unlted States Patent 1 [111 3,910,921

Esanu Oct. 7, 1975 PAPAVERINE MONOPYRIDOXAL [58] Field of Search 260/297P, 297 V, 286 R, PHOSPHATE 260/289 R, 289 A [75] Inventor: Andre Esanu,Paris, France [5 6] References Clted [73] Assignee: S0c iet e dEtudes deProdnits OTHER PUBLICATIONS Chlmlques, Issyles-Moulmeaux, H FranceDlctlonary of Orgamc Compounds, Oxford Unlversrty Press, 1965. [22]Filed: Mar. 6, 1973 2 App] 33 04 Primary ExaminerDonald G. DausAssistant Examiner-David E. Wheeler Related Apphcatlon Data Attorney,Agent, or FirmEyre, Mann & Lucas [63] Continuation-impart of Ser. No.91,550, Nov. 20,

1970, abandoned. ABSTRACT An addition complex of Papaverine, namelyPapaver- 30 l P 1 Forelgn App canon nonty Data ine monopyridoxalphosphate, is described, as well as Jan. 8, France its preparation. Thecompound has in the f l l t 1 th 1 52 U.S. Cl 260/286 R; 260/297.5;424/258 0 Ogy card) Ogy and f pa 0 ogy [51] Int. Cl. C07D 215/58 1Claim, N0 Drawings PAPAVERINE MONOPYRIDOXAL PHOSPHATE This applicationis a continuation-in-part of Ser. No. 91,550, filed Nov. 20, 1970, nowabandoned.

This invention relates to a new compound which is an addition complex ofpapaverine, and which presents an interest in the medical field.

The application discloses an invention providing the compound papaverinemonopyridoxal phosphate, which has the formula:

CHO

The new compound is a yellow product melting at about 125C. lts formulais C H O N P and its molecular weight is 586.54.

The compound of this invention can be obtained by the reaction ofS-pyridoxal phosphoric acid with a suspension of papaverine in water.The reagents are preferably used in equimolar quantities. The followingexample illustrates the invention.

EXAMPLE 33.9 g (0.1 mole) of papaverine were added under stirring to 0.5liter of water in a 2 liter flask. The resulting suspension was heatedto boiling for some minutes, under stirring, then cooled to about 70C.To the suspension there were added 24.7 g (O.l I mole) of 5- pyridoxalphosphoric acid. The stirring was continued until the particles ofpapaverine in suspension had dissolved and the solution thus obtainedwas filtered, then cooled, and the complex precipitated bylyophilisation.

There were obtained 54 g of papaverine monopyridoxal phosphate meltingat about 125C. The analytical values were as follows:

C H O N P Experimental 57.12 5.74 26.81 4.91 5.42 Theoretical (57.34)(5.33) (27.28) (4.77) (5.28)

g/kg). Moreover the in vitro activities of the compound of theinvention, on one hand, and of the association of pyridoxal phosphatepapaverine hydrochloride, on the other hand, show more favorable values,for instance, in the test of the spasmolytic action on isolated ileon ofguinea pig. A peripheral vasodilator action has been noted in the testof the isolated perfused ear of rabbit with more favorable results withpapaverine monopyridoxal phosphate than with papaverine hydrochloride.

In vivo experimentation undertaken on dogs with the new compound hasshown better action in the increase of the coronary and femoral bloodflows, compared with the action of the mixture of pyridoxal phosphatepapaverine hydrochloride.

The results obtained in the previously mentioned pharmacologicalexperimentation have led to develop a drug comprising, as an essentialingredient, this new compound for use in human therapy in the field ofneurology, cardiology and arterial pathology.

This drug can be presented in any form suitable for human therapy andthe retained forms were gelatin capsules dosed at 0.250 g for oraladministration and injectionable solution in phials containing 0.100 gper unit for intraveinous, intraarterial or intramuscularadministration.

Clinical experimentation on patients (about cases) suffering fromcranial traumatisms, cerebral vascular deficiencies, thrombosis,sequelae of hemiplegia, Parkinson s disease, infarctus, angor, arterialhypertension, cardiovascular diseases or affections related with thesame, have given very favorable results, i.e., better or fasterrecovery, without any noticeable side effects.

The daily doses to be administered are in the range of 0.250 g to 3 gper os or 0.1 g to 1.2 g by injection. More usual daily doses are 0.5 gto 1.5 g per os or 0.1 g to 0.6 g by injection.

The advantages of the present invention, as well as certain changes andmodifications of the disclosed embodiment thereof, will be readilyapparent to those skilled in the art. It is the Applicants intention tocover all those changes and modifications which could be made to theembodiment of the invention herein chosen for the purposes of thedisclosure without departing from the spirit and scope of the invention.

What is claimed is: r

1. Papaverine monopyridoxal phosphate.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION PATENT NO. 13,910,921 DATED October 7, 1975 INVENTOR(S) Andre Esanu It is certifiedthat error appears in the above-identified patent and that said LettersPate are hereby corrected as shown below:

Foreign Application Priority Data should read -Jan.8,1970

Gt.Britain 70.919"

C01. 1 Lines 10 to 27: The formula should read Signed and Scaled thistwenty-fourth D ay Of February 1 9 76 [SEAL] Arrest:

RUTH C. MASON C. MARSHALL DANN Allisfing jfife Commissioner uj'Parentsand Trademarks

1. PAPAVERINE MONOPYRIDOXAL PHOSPHATE.